Synthesis of Imidazo[1,2-a]pyridine-Fused 1,3-Benzodiazepine Derivatives with Anticancer Activity via a One-Pot Cascade GBB-3CR/Pd(II)-Catalyzed Azide-Isocyanide Coupling/Cyclization Process.

A new one-pot synthesis of imidazo[1,2-a]pyridine-fused 1,3-benzodiazepine derivatives via a sequential GBB-3CR/Pd(II)-catalyzed azide-isocyanide coupling/cyclization process was developed. The Groebke-Blackburn-Bienaymé three-component reactions (GBB-3CR) of 2-aminopyridine, 2-azidobenzaldehydes, and isocyanides in the presence of a catalytic amount of p-toluenesulfonic acid gave azide intermediates without separation. The reaction was followed by using another molecule of isocyanides to produce imidazo[1,2-a]pyridine-fused 1,3-benzodiazepine derivatives in good yields by the Pd(II)-catalyzed azide-isocyanide coupling/cyclization reaction. The synthetic approach produces novel nitrogen-fused polycyclic heterocycles under mild reaction conditions. The preliminary biological evaluation demonstrated that compound 6a inhibited glioma cells efficiently, suggesting potentially broad applications of the approach for synthesis and medicinal chemistry.

Deep vein thrombosis in a patient with Cronkhite-Canada syndrome: a complex case report.

BACKGROUND: Cronkhite-Canada syndrome (CCS) is a rare disease characterized by generalized gastrointestinal polyps, ectodermal abnormalities and variable gastrointestinal symptoms. Few cases to date have described complications with deep vein thrombosis (DVT). Here we reported a rare case of CCS concomitant with DVT. The patient's clinical details, endoscopic findings, safety, and efficacy are reported. CASE PRESENTATION: A 58-year-old patient was admitted to our hospital with recurrent diarrhea, overall abnormal appearance, including hyperpigmentation, hair loss and onychodystrophy, and multiple polyps distributed along the gastrointestinal tract except the esophagus. After considerable assessment, the patient was diagnosed with CCS. She was also diagnosed with concurrent DVT, nephrotic syndrome, and infectious enteritis during the course of disease. After treatment with a combination of methylprednisolone, mesalazine, antibiotics, rivaroxaban, and nutritional support during the 24 months of following the patient in this case, the clinical manifestations and endoscopic findings reached complete remission two years after the diagnosis. CONCLUSION: To our knowledge, this study is the first case of CCS complicated with DVT reported in China. Although rare, it is important to consider that DVT may occur after CCS and that it is vital to conduct careful follow-up.

Synthesis of 4-Tetrazolyl-Substituted 3,4-Dihydroquinazoline Derivatives with Anticancer Activity via a One-Pot Sequential Ugi-Azide/Palladium-Catalyzed Azide-Isocyanide Cross-Coupling/Cyclization Reaction.

A new one-pot preparation of 4-tetrazolyl-3,4-dihydroquinazolines has been reported. The Ugi-azide reactions of 2-azidobenzaldehydes, amines, trimethylsilyl azide, and isocyanides produced azide intermediates without separation, which were treated with isocyanides to give 4-tetrazolyl-3,4-dihydroquinazoline derivatives through a sequential Palladium-catalyzed azide-isocyanide cross-coupling/cyclization reaction in moderate to good yields. The biological evaluation demonstrated that compound 6c inhibited breast cancer cells well and displayed broad applications for synthesis and medicinal chemistry.

Zircon record of an Archaean crustal fragment and supercontinent amalgamation in quaternary back-arc volcanic rocks.

Magmatism has profoundly influenced the evolution of the geosphere, hydrosphere, atmosphere, and biosphere in back-arc basins. However, the timing of the magmatism in the Okinawa Trough (OT) is not well constrained by the age spectra of zircons. Here, for the first time, we carry out an integrated study combining in situ analysis of zircon U-Th-Pb and Hf-O isotopes, and trace element compositions of zircons from the volcanic rocks from the southernmost part of the OT. We found that the young (< 100 ka) zircons in these volcanic rocks have old (108 Ma to 2.7 Ga) inherited cores, which were captured as the magma ascended through the rifting continental crust. In particular, the inherited Archean zircons strongly suggest that remnants of the old East Asian continental blocks underlie the embryonic crustal rifting zone. Moreover, the ages of most of the inherited zircons correspond to five supercontinent amalgamation events. Specifically, the Archaean inherited zircons, which have positive εHf(t) and low δ18O values, correspond to the formation of juvenile continental crust. In contrast, the negative εHf(t) and high δ18O values of the post-Archaean inherited zircons indicate that their parental magma contained recycled older crust due to the enhanced crust-mantle interactions during the evolution of the early continental crust. Therefore, the inherited zircons in the back-arc volcanic rocks not only reflect the evolution of the local magmatism, but they also contain a record of the Archaean crustal fragment and of several global continental amalgamation events.

Synthesis and antiphytoviral activity of α-aminophosphonates containing 3, 5-diphenyl-2-isoxazoline as potential papaya ringspot virus inhibitors.

α-Aminophosphonates compounds containing 3,5-diphenyl-2-isoxazoline were synthesized and evaluated for their bioactivity. Seventeen of them showed good bioactivity (protection effect > 50%) in vivo against papaya ringspot virus, while two of them (V29 and V45) exhibited excellent antiviral activity (both 77.8%). In the latter case, the antiviral activity was close to that of antiphytovirucides ningnanmycin and dufulin (both 83.3%) at 500 mg/L. The preliminary structure-activity relationships indicated that the bioactivity was strongly influenced by the substituents.

[Macrophages depletion impairs skeletal muscle regeneration by regulating inflammation and oxidative stress levels].

The objective of this study was to explore the roles of macrophages in the regeneration of injured skeletal muscle and the mechanisms involved. Mice were randomly divided into the following groups: muscle contusion (S), muscle contusion control (SCon), macrophages depleted (T) and macrophages depleted control (TCon) groups. Muscle contusion model was created by high-energy blunt injury. Macrophages depletion model was constructed by injection of clodronate-liposomes. Their gastrocnemius muscles were harvested at the time points of 1, 3, 7 and 14 d post-injury. The changes in skeletal muscle morphology were assessed by hematoxylin-eosin (HE) staining and Masson's trichrome staining. The mRNA and protein levels of inflammatory cytokines, chemokines and oxidative stress factors were analyzed by real-time polymerase chain reaction (RCR) and Western blotting, respectively. HE staining results showed that a small amount of regenerating myofibers were observed in the S group (14 d post-injury), whereas a large number of regenerating muscle fibers were observed in the T group. Quantitative analyses showed that the sizes of regenerating myofibers were significantly smaller in the T group as compared with the S group at 14 d post-injury (P < 0.05). At the same time, Masson staining results showed that macrophage depletion significantly increased the area of fibrosis as compared with the S group at 14 d post-injury (P < 0.01). The expression levels of inflammatory cytokines, chemokines, and oxidative stress factors were increased significantly after muscle injury. Moreover, macrophage depletion increased the expressions of inflammatory cytokines, chemokines and oxidative stress factors as compared with the S group during the later stage of injury (7-14 d post-injury). These results suggest that macrophages depletion can aggravate fibrosis and impair muscle regeneration, and inflammatory cytokines, chemokines and oxidative stress factors may be involved in this process.

Recent advances of imidazole-containing derivatives as anti-tubercular agents.

Tuberculosis still remains one of the most common, communicable, and leading deadliest diseases known to mankind throughout the world. Drug-resistance in Mycobacterium tuberculosis which threatens to worsen the global tuberculosis epidemic has caused great concern in recent years. To overcome the resistance, the development of new drugs with novel mechanisms of actions is of great importance. Imidazole-containing derivatives endow with various biological properties, and some of them demonstrated excellent anti-tubercular activity. As the most emblematic example, 4-nitroimidazole delamanid has already received approval for treatment of multidrug-resistant tuberculosis infected patients. Thus, imidazole-containing derivatives have caused great interests in discovery of new anti-tubercular agents. Numerous of imidazole-containing derivatives were synthesized and screened for their in vitro and in vivo anti-mycobacterial activities against both drug-sensitive and drug-resistant Mycobacterium tuberculosis pathogens. This review aims to outline the recent advances of imidazole-containing derivatives as anti-tubercular agents, and summarize the structure-activity relationship of these derivatives. The enriched structure-activity relationship may pave the way for the further rational development of imidazole-containing derivatives as anti-tubercular agents.

[Protective effects of spirulina on hippocampal injury in exercise-fatigue mice and its mechanism].

OBJECTIVE: To investigate the roles of BDNF/TrkB neurotrophic signaling in hippocampal injury for fatigue rats induced by incremental load exercise and the protective effects and mechanism of spirulina supplement. METHODS: Sixty SD rats were randomly divided into normal control group (NC), normal plus spirulina group(NS), exercise model group (EM), exercise plus spirulina group (ES), and positive control group (PC), 12 rats in each group.Group EM, Group ES and Group PC were applied by treadmill running with high-intensity increasing for three weeks, and Group NC had not any intervention measures.Group ES and Group NS were treated with spirulina at a dose of 300 mg/kg.bw.by intragastric administration.Group PC was gavaged at the same volume of ginseng extract of 1.92 g/kg for three weeks.The expressions of brain-derived neurotrophic factor (BDNF), tyrosine kinase recptor (TrkB), phospho-tyrosine kinase recptor (p-TrkB) were tested by Western blot and immunohistochemical method, and micromorphology changes of hippocampal CA1 were observed by light microscope at the end of the experiment.The general situations of rats such as body weights were recorded during the experiment. RESULTS: Compared with Group NC, Group EM showed significantly decrease in body weight and hippocampal CA1 neurons of the group loosely arrayed and disarrayed and some neurons were shrinked, and even some neurons disappeared.The expressions of BDNF, TrkB and p-TrkB in group EM were increased significantly(P<0.01).Compared with Group EM, body weight of Group ES was increased significantly, and the above mentioned injuries of neurons were improved significantly:the number of neurons and nissl bodies were significantly increased and the neurons arrayed regularly and its morphology was more complete.The expressions of BDNF, TrkB and p-TrkB in the group were increased significantly(P<0.05 or P<0.01).And there was no difference between Group ES and Group PC. CONCLUSIONS: BDNF/TrkB neurotrophic signal pathway could be involved in the repair process of hippocampal nervous damage caused by incremental load exercise for fatigue rats.Spirulina supplement had a protective effect on the damaged nervous through increasing the expressions of BDNF, TrkB and p-TrkB.

Impulsive Multisynchronization of Coupled Multistable Neural Networks With Time-Varying Delay.

This paper studies the synchronization problem of coupled delayed multistable neural networks (NNs) with directed topology. To begin with, several sufficient conditions are developed in terms of algebraic inequalities such that every subnetwork has multiple locally exponentially stable periodic orbits or equilibrium points. Then two new concepts named dynamical multisynchronization (DMS) and static multisynchronization (SMS) are introduced to describe the two novel kinds of synchronization manifolds. Using the impulsive control strategy and the Razumikhin-type technique, some sufficient conditions for both the DMS and the SMS of the controlled coupled delayed multistable NNs with fixed and switching topologies are derived, respectively. Simulation examples are presented to illustrate the effectiveness of the proposed results.

[Application of area percent of positive neuron and relative intensity of staining grey level in the image quantitative analysis of rat brain tissues immunohistochemistry].

OBJECTIVE: The acetylcholine expression in hypothalamus arcuate nucleus is detected and then the images are processed and analyzed. The features of the image quantitative analysis of immunohistochemistry (IHC) with the method combining two parameters of area percent of positive neuron (APPN) and relative intensity of staining grey level (RISGL) were investigated. METHODS: Samples were the im-munohistochemical slices of acetylcholine(ACh)expression of hypothalamic arcuate nucleus cholinergic neurons in the process of exercise in-duced immunosuppression, which included twelve groups of "0 w, 2 w, 4 w, 6 w" and three groups of "control, immediately after exercise, 3 hours after exercise" in every week. IHC technology was used to detect the ACh expression. The image quantitative analysis of IHC was con-ducted in accordance with the parameters of ACh total area of positive neuron (TAPN), average intensity of staining grey level (AISGL), APPN, RISGL, APPN/RISGL. Then the differences among APPN, RISGL and traditional parameters in the quantitative analysis were com-pared and the advantages were found. RESULTS: The changes of TAPN and APPN showed almost the same variation. Namely the corresponding significant differences could be found through these two parameters(P < 0.05), but the sensitivity and anti-interference of APPN was higher. The results of AISGL and RISGL were not coincident completely. Furthermore, with the combination of APPN and RISGL, the positive expres-sion could be reflected better than any single parameter. CONCLUSIONS: The parameters of immunohistochemical image analysis, APPN and RIS-GL, can be reliable and accurate in image quantitative analysis of IHC. The combination of APPN and RISGL can not only reflect the expres-sion of positive neurons, but also help analyze its mechanism, which is better than traditional analysis parameters.

First Comparative Analysis of the Community Structures and Carbon Metabolic Pathways of the Bacteria Associated with Alvinocaris longirostris in a Hydrothermal Vent of Okinawa Trough.

Alvinocaris longirostris is a species of shrimp existing in the hydrothermal fields of Okinawa Trough. To date the structure and function of the microbial community associated with A. longirostris are essentially unknown. In this study, by employment of the techniques of high through-put sequencing and clone library construction and analysis, we compared for the first time the community structures and metabolic profiles of microbes associated with the gill and gut of A. longirostris in a hydrothermal field of Okinawa Trough. Fourteen phyla were detected in the gill and gut communities, of which 11 phyla were shared by both tissues. Proteobacteria made up a substantial proportion in both tissues, while Firmicutes was abundant only in gut. Although gill and gut communities were similar in bacterial diversities, the bacterial community structures in these two tissues were significantly different. Further, we discovered for the first time the existence in the gill and gut communities of A. longirostris the genes (cbbM and aclB) encoding the key enzymes of Calvin-Benson-Bassham (CBB) cycle and the reductive tricarboxylic acid (rTCA) cycle, and that both cbbM and aclB were significantly more abundant in gill than in gut. Taken together, these results provide the first evidence that at least two carbon fixation pathways are present in both the gill and the gut communities of A. longirostris, and that the communities in different tissues likely differ in autotrophic productivity.

Comparative analysis of chemical constituents, antimicrobial and antioxidant activities of ethylacetate extracts of Polygonum cuspidatum and its endophytic actinomycete, Streptomyces sp. A0916.

The present study investigated the chemical composition of ethylacetate extracts from an endophytic actinomycete Streptomyces sp. A0916 and its host Polygonum cuspidatum. A comparative analysis of the antimicrobial and antioxidant properties of the extracts was also conducted. 32 compounds of P. cuspidatum and 23 compounds of Streptomyces sp. A0916 were isolated and identified by GC/MS. Antimicrobial activities of the extracts were evaluated using eight microbial strains (3 Gram-positive bacteria, 3 Gram-negative bacteria, and 2 fungi). The Streptomyces sp. A0916 extracts showed a wide range of antimicrobial activities and presented greater antimicrobial effectiveness than the P. cuspidatum extracts. The minimum inhibitory concentration (MIC) of Streptomyces sp. A0916 extracts against the ampicillin-resistant strain Enterococcus faecium SIIA843 was 32 µg·mL(-1). Furthermore, the extracts had greater antimicrobial effect against Gram-positive bacteria than Gram-negative bacteria. Finally, the antioxidant activity of the Streptomyces sp. A0916 extracts was equal to that of the P. cuspidatum extracts. In conclusion, our results suggest that the endophytic actinomycetes of the medicinal plants are an important source of bioactive substances.

Erwinia teleogrylli sp. nov., a Bacterial Isolate Associated with a Chinese Cricket.

A bacterial isolate (SCU-B244T) was obtained in China from crickets (Teleogryllus occipitalis) living in cropland deserted for approximately 10 years. The isolated bacteria were Gram-negative, facultatively anaerobic, oxidase-negative rods. A preliminary analysis of the 16S rRNA gene sequence indicated that the strain belongs to either the genus Erwinia or Pantoea. Analysis of multilocus sequence typing based on concatenated partial atpD, gyrB and infB gene sequences and physiological and biochemical characteristics indicated that the strain belonged to the genus Erwinia, as member of a new species as it was distinct from other known Erwinia species. Further analysis of the 16S rRNA gene showed SCU-B244T to have 94.71% identity to the closest species of that genus, Erwinia oleae (DSM 23398T), which is below the threshold of 97% used to discriminate bacterial species. DNA-DNA hybridization results (5.78±2.52%) between SCU-B244T and Erwinia oleae (DSM 23398T) confirmed that SCU-B244T and Erwinia oleae (DSM 23398T) represent different species combined with average nucleotide identity values which range from 72.42% to 74.41. The DNA G+C content of SCU-B244T was 55.32 mol%, which also differs from that of Erwinia oleae (54.7 to 54.9 mol%). The polyphasic taxonomic approach used here confirmed that the strain belongs to the Erwinia group and represents a novel species. The name Erwinia teleogrylli sp. nov. is proposed for this novel taxon, for which the type strain is SCU-B244T (= CGMCC 1.12772T = DSM 28222T = KCTC 42022T).

Microbial diversity in the deep-sea sediments of Iheya North and Iheya Ridge, Okinawa Trough.

In this study, we analyzed the bacterial and archaeal diversities of the deep-sea sediments in Iheya North and Iheya Ridge, Okinawa Trough, using the high-throughput sequencing technology of Illumina MiSeq 2500 platform. Four samples (IN1, IN2, IR1 and IR2) were used in this study, of which IN1 and IN2 were located at regions close to and distant, respectively, from the active hydrothermal vents in Iheya North, while IR1 and IR2 were located at regions close to and distant, respectively, from the active hydrothermal vents in Iheya Ridge. The four samples were rich in different metal elements. Sequence analysis based on the V3-V4 regions of 16S rDNA gene obtained 170,363 taxon tags, including 122,920 bacterial tags and 47,433 archaeal tags, which cover 31 phyla, 50 classes, 59 orders, 87 families, and 138 genera. Overall, the microbial communities in all samples were dominated by bacteria, in which Proteobacteria was the largest phylum, followed by Chloroflexi, Firmicutes, Acidobacteria, Actinobacteria, Gemmatimonadetes, and Nitrospirae, which together accounted for 64.6% of the total taxon tags. In contrast to the high bacterial diversities, the archaeal diversity was low and dominated by Thaumarchaeota, which accounted for 22.9% of the total taxon tags. Comparative analysis showed that (i) IN2 and IR2 exhibited more microbial richness than IN1 and IR1, (ii) IR1 and IR2 exhibited higher microbial diversities than IN1 and IN2, (iii) samples from Iheya Ridge and Iheya North fell into two groups based on principle component analysis. Furthermore, microbes potentially involved in sulfur, nitrogen, and metal metabolism and cycling were detected in all samples. These results provide for the first time a comparative picture of the microbial diversities in the sediments of Iheya North and Iheya Ridge and indicate that geological features and distance from active hydrothermal vents likely play important roles in the shaping of microbial community structure.

Diversity, bioactivities, and metabolic potentials of endophytic actinomycetes isolated from traditional medicinal plants in Sichuan, China.

The present study was designed to determine the taxonomic diversity and metabolic activity of the actinomycetes community, including 13 traditional medicinal plants collected in Sichuan province, China, using multiple approaches such as morphological and molecular identification methods, bioactivity assays, and PCR screening for genes involved in antibiotics biosynthesis. 119 endophytic actinomycetes were recovered; 80 representative strains were chosen for 16S rRNA gene partial sequence analyses, with 66 of them being affiliated to genus Streptomyces and the remaining 14 strains being rare actinomycetes. Antimicrobial tests showed that 12 (15%) of the 80 endophytic actinomycetes displayed inhibitory effects against at least one indicator pathogens, which were all assigned to the genus Streptomyces. In addition, 87.5% and 58.8% of the isolates showed anticancer and anti-diabetic activities, respectively. Meanwhile, the anticancer activities of the isolates negatively correlated with their anti-diabetic activities. Based on the results of PCR screening, five genes, PKS-I, PKS-II, NRPS, ANSA, and oxyB, were detected in 55.0%, 58.8%, 90.0%, 18.8% and 8.8% of the 80 actinomycetes, respectively. In conclusion, the PCR screening method employed in the present study was conducive for screening and selection of potential actinomycetes and predicting potential secondary metabolites, which could overcome the limitations of traditional activity screening models.

[Expression of human pituitary tumor transforming gene 1 in colorectal cancer detected with real-time fluorescent quantitative PCR and its clinical significance].

BACKGROUND & OBJECTIVE: Although human pituitary tumor transforming gene 1 (hPTTG1) is overexpressed in malignant tumors such as colorectal cancer, its correlation to clinicopathologic parameters and its value in diagnosis and prognosis prediction of colorectal cancer are still not clear. We investigated the expression of hPTTG1 in colorectal cancer tissues, and elucidated its correlation to some clinicopathologic parameters of colorectal cancer. METHODS: The expression of hPTTG1 in 60 specimens of colorectal cancer and corresponding noncancerous tissues were examined with real-time fluorescent quantitative polymerase chain reaction, and its correlation to seven clinicopathologic parameters were analyzed. RESULTS: The mRNA level of hPTTG1 was significantly higher in colorectal cancer tissues than in corresponding noncancerous tissues (0.42+/-0.07 vs. 0.03+/-0.01, P<0.001), significantly higher in colorectal cancer tissues with serum CEA level of > 5 ng/mL than in those with CEA of < 5 ng/mL (22.79+/-7.42 vs. 9.34+/-2.61, P<0.001), significantly higher in colorectal cancer tissues with diameter of > or = 3.5 cm than in those with diameter of < 3.5 cm (15.80+/-8.80 vs. 10.91+/-5.22, P<0.05), significantly lower in Dukes'A, B tumors than in Dukes' C, D tumors (9.03+/-0.35 and 9.58+/-2.93 vs. 15.88+/-8.09 and 25.69+/-7.67, P<0.001), and significantly higher in colorectal cancer tissues with lymph node metastasis (17.63+/-8.47), liver metastasis (31.07+/-4.10) and other organ metastasis (22.78+/-6.39) than in those without metastasis (11.15+/-6.65) (P<0.001). hPTTG1 expression had no relationship with patients' age, sex and histological type (P>0.05). CONCLUSIONS: hPTTG1 is overexpressed in colorectal cancer. It is closely related to the progression of colorectal cancer, and may be helpful for prognosis prediction of colorectal cancer.

A simple method for AFM tip characterization by polystyrene spheres.

An AFM image would not be the true topography of a surface because of the limitation of a finite size of the tip. The true topography of the surface can be deduced if we can know the tip shape. In this paper a simple method has been established to determine the profile of an AFM tip. A geometrical model for the tip and a spherical object has been proposed to show the procedure for deducing the tip shape from AFM images. Isolated spheres and closely packed spheres with different diameters have been observed to confirm the tip shape by this method. It is a non-destructive method to determine the tip shape and the results can be used for future reconstruction of an AFM image.